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Biomedical subjects

Stephen P Dunn

Publications and source records attributed to Stephen P Dunn.

12 recordsLinked to original sources
PubMed2007

Successful liver transplant for unresectable hepatoblastoma.

BACKGROUND: Treatment of children with stage III and IV hepatoblastoma has shown little improvement with 5-year survival rates of 64% and 25%, respectively (J Clin Oncol 2000;18:2665-75). A timely and organized treatment program including preoperative chemotherapy combined with living donor liver transplantation and postoperative chemotherapy has been used seeking improved long-term survival in stage III and IV cases. METHODS: A retrospective review of 8 patients with stage III and IV hepatoblastoma unresectable by conventional resection were treated with complete hepatectomy and transplantation. Approval was obtained from our institutional review board. RESULTS: Since August of 2001, we have treated 6 patients with stage III hepatoblastoma and 2 patients with initial stage IV hepatoblastoma. These patients (age, 23 months-9 years) had all received extensive chemotherapy or prior resections. After chemotherapy, none had gross tumor documented outside of the liver at time of transplantation. All underwent hepatectomy including vena cava resection, in selected cases, with living donor orthotopic liver transplantation. All patients had at least 2 cycles of postoperative chemotherapy. Of 8 patients, 6 are alive and well with normalized alpha-fetoprotein levels. There were 2 late deaths from recurrent disease. Length of follow-up ranged from 7 to 53 months. CONCLUSION: Complete hepatectomy with living donor liver transplantation provides optimal surgical treatment in unresectable stage III and initial stage IV disease confined to the liver at resection. This series indicates that children tolerate complete hepatectomy, transplantation, and postoperative chemotherapy well. Referral to a transplant center during the first 3 cycles of chemotherapy appears to offers the best opportunity for long-term survival.

Antineoplastic Agents↗
PubMed2006

c-Myc inhibition negatively impacts lymphoma growth.

BACKGROUND: Proto-oncogene c-Myc dysregulation is commonly found in aggressive tumors. Dysregulation is central to lymphomagenesis in Burkitt lymphoma and other non-Hodgkin's lymphomas. This suggests targeting c-Myc as a treatment for myc-associated malignancies. METHODS: Microarrays showed c-Myc dysregulation in a B-lymphoblastoid line, TIB-215. This was confirmed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and extended to 3 additional Burkitt lymphoma lines. Growth effects of a c-Myc inhibitor, compound 10058-F4, were determined in these 4 lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analyses and direct cell counts. Drug effects on c-Myc gene expression levels were measured using minor groove binding-TaqMan real-time reverse transcriptase-polymerase chain reaction. Drug specificity was analyzed in rat c-Myc knockout (-/-) and Myc-transfected cells. RESULTS: c-Myc dysregulation was shown to be cell-cycle independent without rapid decay of c-Myc mRNA levels in all 4 lines. Using a c-Myc inhibitor, we found that growth inhibition was time- and dose-dependent. This inhibition caused unexpected downregulation (> or =65%) of c-Myc mRNAs. CONCLUSIONS: The inhibition of c-Myc decreased growth in aggressive lymphoma cells. This mechanism included c-Myc mRNA downregulation and dissociation of c-Myc/Max protein heterodimer. These results support targeting c-Myc in tumors with high morbidity and mortality.

Animals↗
PubMed2006

Analysis of Epstein-Barr virus reservoirs in paired blood and breast cancer primary biopsy specimens by real time PCR.

INTRODUCTION: Epstein-Barr virus (EBV) is present in over 90% of the world's population. This infection is considered benign, even though in limited cases EBV is associated with infectious and neoplastic conditions. Over the past decade, the EBV association with breast cancer has been constantly debated. Adding to this clinical and biological uncertainty, different techniques gave contradictory results for the presence of EBV in breast carcinoma specimens. In this study, minor groove binding (MGB)-TaqMan real time PCR was used to detect the presence of EBV DNA in both peripheral blood and tumor samples of selected patients. METHODS: Peripheral blood and breast carcinoma specimens from 24 patients were collected. DNA was extracted and then amplified by MGB-TaqMan real time PCR. RESULTS: Of 24 breast tumor specimens, 11 (46%) were positive for EBV DNA. Of these 11 breast tumor specimens, 7 (64%) were also positive for EBV DNA in the peripheral blood, while 4 (36%) were positive for EBV DNA in the tumor, but negative in the blood. CONCLUSION: EBV was found at extremely low levels, with a mean of 0.00004 EBV genomes per cell (range 0.00014 to 0.00001 EBV genomes per cell). Furthermore, our finding of the presence of EBV in the tumor specimens coupled to the absence of detection of EBV genomic DNA in the peripheral blood is consistent with the epithelial nature of the virus. Because of the low levels of viral DNA in tumor tissue, further studies are needed to assess the biological input of EBV in breast cancer.

Adult↗
PubMed2006

Intussusception in a child with respiratory syncytial virus: a new association.

Intussusception is known to be associated with childhood viral illnesses. Respiratory syncytial virus (RSV) has not, to our knowledge, been previously reported in association with intussusception. We report a case of a 4-month-old boy admitted with RSV bronchiolitis, who subsequently developed an intussusception during the hospital course, necessitating laparotomy and resection.

Comorbidity↗
PubMed2005

Liver transplantation as definitive treatment for a factor V Leiden mutation.

Liver transplantation (LT) was achieved for factor V Leiden-induced thrombophilia in a neonate with hepatic veno-occlusive disease. Initial LT was performed with a liver segment removed from a child with primary oxalosis. Four months later, a second, definitive LT was performed. The child remains well without recurrent thrombosis.

Factor V↗
PubMed2004

Improvement in renal function and rejection control in pediatric liver transplant recipients with the introduction of sirolimus.

Calcineurin inhibitors have dramatically improved the outcomes of pediatric liver transplantation. However, calcineurin inhibitor use is associated with a 50% reduction in glomerular filtration rate in the first year post-transplant. Nephrotoxicity can be difficult to manage, especially in the pediatric population. We hypothesized that the addition of an mTOR inhibitor with decreased calcineurin inhibitor levels might improve or prevent renal insufficiency and improve control of rejection. A retrospective chart review was performed on the patients treated with sirolimus who had undergone an orthotopic liver transplant between January 2000 and February 2003. Thirty-eight patients were identified. Mean age was 8.6 yr. Fourteen patients were male and 24 were female. Mean weight was 30.3 kg. The most common indications for starting sirolimus were rejection (42%) and renal impairment (29%). Seventy-three percent of patients begun on sirolimus remain on the medication. Those with renal impairment (11 patients) showed improvement in their creatinine levels from a mean baseline of 1.3 to 0.8 mg/dL. Their calculated creatinine clearance (Schwartz formula) improved from 63.7 to 84.8 mL/min (p = 0.03). Patients started on sirolimus for rejection showed significant improvement in hepatocellular enzymes despite a reduction in the tacrolimus level from 12.2 to 7.5 ng/mL. The mean alanine aminotransferase level improved from 221 to 100 units/L (p = 0.02), and the mean aspartate aminotransferase improved from 121 to 99 units/L (p = 0.59). Addition of sirolimus to a tacrolimus-based regimen with lower target tacrolimus levels improved liver function in patients with rejection. Addition of sirolimus significantly improved renal function as shown by creatinine level and calculated creatinine clearance in those children with renal impairment. The effect of combined immunosuppressant treatment with tacrolimus and sirolimus on long-term renal function needs to be evaluated.

Adolescent↗
PubMed2003

Neoral monitoring 2 hours post-dose and the pediatric transplant patient.

Cyclosporin A therapy has evolved greatly over the past 25 years of clinical experience. Sophisticated studies of CsA pharmacokinetics and pharmacodynamics have led to a better understanding of the relationship between dose response and biological effect. It has become apparent that achieving target drug exposure is necessary for optimal clinical outcomes. Monitoring dose response has become a key aspect of immunosuppressive management. This review presents the information available supporting cyclosporin drug concentration drawn two hours post dose (C-2) in children who have been transplanted as the best single indicator of CsA exposure. Further studies evaluating the clinical benefit of achieving C-2 targets in children are indicated.

Child↗
PubMed2002

Domino as a bridge to definitive liver transplantation in a neonate.

An interim liver transplant was used to extend survival in a neonate. This was accomplished by the initial transplant of a left-lateral segment of a metabolically abnormal liver obtained from a 7-yr-old patient with primary oxalosis. This bridging strategy was required because our neonatal patient was dying of fulminant hepatic failure caused by hepatic vein thrombosis and a small liver or liver segment could not be found. Although problems with hyperoxaluria were encountered in the neonate post-transplant, the interim liver transplant enabled the baby to survive and grow until the age of 4 months. At that time, a definitive transplant was performed using the left-lateral segment of his mother's liver. This case represents the first reported use of a pediatric domino transplant where a metabolically abnormal liver was used to allow sufficient growth to permit a definitive liver transplantation.

Child↗
PubMed2002

Basiliximab in pediatric liver transplantation: a pharmacokinetic-derived dosing algorithm.

The pharmacokinetics and immunodynamics of basiliximab were assessed in 37 pediatric de novo liver allograft recipients to rationally design a dose regimen for this age-group. In part one of the study, patients were given 12 mg/m2 basiliximab by bolus intravenous injection after organ perfusion and on day 4 after transplant. An interim pharmacokinetic evaluation supported a fixed-dose approach for part two of the study in which infants and children received two 10-mg doses of basiliximab and adolescents received two 20-mg doses. Blood samples were collected over a 12-week period for screening for anti-idiotype antibodies and analysis of basiliximab and soluble interleukin-2 receptor (IL-2R) concentrations. Basiliximab clearance in infants and children < 9 yr of age (n = 30) was reduced by approximately 50% compared with adults from a previous study and was independent of age to 9 yr, weight to 30 kg, and body surface area to 1.0 m2. Clearance in children and adolescents 9-14 yr of age (n = 7) approached or reached adult values. An average of 15% of the dose was eliminated via drained ascites fluid, and drug clearance via this route averaged 29% of total body clearance. Patients with > 5 L of ascites fluid drainage tended to have lower systemic exposure to basiliximab. CD25-saturating basiliximab concentrations were maintained for 27 +/- 9 days in part one of the study (mg/m2 dosing) with infants exhibiting the lowest durations. CD25 saturation lasted 37 +/- 11 days in part two of the study, based on the fixed-dose regimen (p = 0.004 vs. mg/mg2 dosing), but did not show the age-related bias observed in part one of the study. Anti-idiotype antibodies were detected in four patients, but this did not influence the clearance of basiliximab or duration of CD25 saturation. All 40 enrolled patients were included in the intent-to-treat clinical analysis. Episodes of acute rejection occurred in 22 patients (55%) during the first 12 months post-transplant. Three patients experienced loss of their graft as a result of technical complications, and six patients died during the 12-month study. Basiliximab was well tolerated by intravenous bolus injection, with no cytokine-release syndrome or other infusion-related adverse events. Hence, basiliximab was safe and well tolerated in pediatric patients undergoing orthotopic liver transplantation. To achieve similar basiliximab exposure as is efficacious in adults, pediatric patients < 35 kg in weight should receive two 10-mg doses and those > or = 35 kg should receive two 20-mg doses of basiliximab by intravenous infusion or bolus injection. The first dose should be given within 6 h after organ perfusion and the second on day 4 after transplantation. A supplemental dose may be considered for patients with a large volume of drained ascites fluid relative to body size.

Adolescent↗